Ischemic cardiovascular disease, the leading cause of death in industrialized societies, can be frequently preceded by the rupture of unstable atherosclerotic plaque. The intricate interplay between biomechanical, compositional and morphological factors may influence plaque stability. Certain exemplary techniques that facilitate a composite understanding of the link between these factors can assist in identifying rupture-prone plaques, guiding treatment and for investigating mechanisms associated with plaque stabilization therapies.
Another technique has been investigated, i.e., a Laser Speckle Imaging (“LSI”) technique which can provide measurements related to biomechanical, compositional and morphological factors potentially yielding an advantageous technique for detecting high-risk plaques in patients. Laser speckle is a granular pattern formed by the interference of coherent laser light scattered from tissue. The speckle pattern is dynamically modulated by Brownian motion of endogenous particles within tissue, which is governed by the viscoelasticity of tissue. In LSI, the extent of Brownian motion can be quantified by the cross-correlation of speckle images obtained as a function of time. The exemplary techniques of using arterial specimens ex vivo have demonstrated that the index of viscoelasticity measured by LSI can be related to plaque type, structure and composition.
While exemplary prior ex vivo studies can indicate an advantageous diagnostic potential of LSI, important technical challenges may exist in extending LSI technology and techniques for an intracoronary in vivo use. In order to achieve clinical viability, the exemplary intracoronary LSI system and technique can, e.g., (a) facilitate a rapid screening of long coronary segments (e.g., ˜5 cm) to identify high-risk plaques, (b) obtain diagnostic information in the presence of coronary blood flow, and (c) retain an adequate motion stability over the cardiac cycle.
Atherosclerotic Plaque:
Despite widespread efforts towards its detection and therapy, thrombus mediated ischemic cardiovascular disease still remains the leading cause of mortality in industrialized societies. The rupture of unstable coronary atherosclerotic plaque frequently precedes a majority of ischemic cardiovascular events. It is believed that a certain type of plaque, termed the necrotic-core fibroatheroma (NCFA) is particularly vulnerable to rupture. Typical characteristics of vulnerable NCFA's include the presence of a thin (<65 μm), mechanically weak fibrous cap, a large compliant necrotic core, and activated macrophages near the fibrous cap.1,2 It is recognized that a complex liaison between biomechanical, compositional and morphological mechanisms influences plaque stability. These mechanisms can include the proteolysis of fibrous cap collagen by matrix metalloproteinases (MMP) released by activated macrophages and apoptosis of intimal SMC's, which impedes collagen synthesis.3,4,5 Mediated by endothelial production of nitric oxide, TGF-β, and plasmin, this dynamic imbalance between collagen synthesis and degradation causes a net reduction in collagen content and mechanically weakens the fibrous cap.6 Systemic statin therapy likely favorably reverses these factors and stabilizes plaques, thereby dramatically reducing the incidence of acute coronary events.7,8,9,10,11 
Evidence suggesting that biomechanical factors play an important part in determining plaque stability is compelling. Differential shear stresses can induce focal variations in plaque composition, influencing susceptibility to plaque rupture, atherosclerosis progression and coronary thrombosis.6 Finite element studies have suggested that rupture of the fibrous cap is greatly influenced by regions of high circumferential stress typically in the lateral cap shoulders.12,13,14 Computational and experimental analyses have demonstrated that local stress distributions are affected by atheroma structure and material properties,15 and higher differential strain is measured in lipid rich tissue.16 The accumulation of a compliant lipid pool influences the local stress distributions within the plaque resulting in rupture of the fibrous cap.2,12 Cyclic mechanical strain within the arterial wall affects macrophage gene expression and SMC proliferation.17 Histology studies have shown the localization of matrix metalloproteinase-1 (MMP-1) in regions of high circumferential strain within plaques, suggesting that mechanical stress/strain influences MMP release and weakens plaque structure.18 The exemplary processes leading to plaque vulnerability and the therapeutic mechanisms contributing to plaque stabilization are multi-factorial, and techniques that allow a composite understanding of these factors are invaluable for identifying rupture-prone plaques, guiding treatment and for providing insights regarding mechanisms associated with plaque stabilization therapies.
Detecting Unstable Coronary Plaques: A variety of catheter-based imaging methods such as IVUS, magnetic resonance imaging (MRI), angioscopy, thermography, infrared and Raman spectroscopy, and optical coherence tomography (OCT) have been investigated for identifying unstable plaque.19,20,21,22,23,24,25,26,27,28,29 These exemplary methods are complementary to techniques that measure biomechanical properties, since they provide important structural and compositional information associated with plaque stability. To address the likely need for evaluating plaque biomechanical properties, IVUS-based elastography has been developed to compute local strain in atherosclerotic plaque in response to intra-luminal pressure differentials exerted on the arterial wall.16,30 In IVUS elastography, arterial tissue deformation may be estimated using cross-correlation analysis and strains are computed from the tissue velocity gradient. Exemplary approaches utilized for IVUS elastography can be applied to OCT to provide higher spatial resolution of strain estimation and enhanced tissue contrast relative to IVUS.31 Such exemplary methods for strain imaging using elastography enable the measurement of arterial response to a dynamic external loading environment, providing an indirect evaluation of intrinsic tissue compliance, which depends on tissue viscoelasticity. However, a measurement of plaque viscoelasticity with these approaches may be challenging, generally using a priori knowledge of the microscopic plaque morphology and loading conditions to solve the inverse problem.
Brownian Motion and Viscoelasticity:
The passive dynamics of particles suspended in a viscoelastic material may be potentially of significant utility in evaluating the bulk mechanical properties of the medium. In 1827, Robert Brown observed and noted that small particles suspended in a viscous medium ceaselessly move about following a random path. This effect, termed as Brownian motion, can be caused due to the thermal motion of molecules which incessantly bombard suspended particles within the medium, causing random particular motion. Mason and Weitz demonstrated that the Brownian motion of suspended particles is intimately related to the structure and viscoelastic properties of the suspending medium, and suspended particles exhibit larger range of motions when their local environment is less rigid.32 Exemplary studies have shown that the viscoelastic modulus of polymer materials can be evaluated by suspending exogenous microspheres and measuring the time scale and mean square displacement of microscopic trajectories using diffuse light scattering techniques.33 Yamada et al measured the viscoelastic properties of living cells from the Brownian motion of endogenous granules suspended within the cytoskeletal network.34 By applying these concepts a further optical technique has been investigated, termed Laser Speckle Imaging, which analyzes the intrinsic Brownian motion of endogenous microscopic particles suspended within atherosclerotic plaques to possibly evaluate plaque viscoelasticity.
Laser Speckle Imaging of Atherosclerotic Plaques:
When an object is imaged using highly coherent light from a laser, a granular pattern of multiple bright and dark spots becomes apparent on the image, which bears no perceptible relationship to the macroscopic structure of the object, as shown in FIG. 1. These random intensity patterns, known as laser speckle,35 can occur in two situations, e.g., (i) when coherent light is reflected from a surface which is rough on the scale of an optical wavelength, and (ii) when coherent light propagates through and is scattered by a medium with random refractive index fluctuations such as in tissue.
The interference of light returning from the random surface or medium generally causes laser speckle. Laser speckle formed from scattering within tissue is exquisitely sensitive to Brownian motion. The Brownian motion of endogenous light scattering particles in tissue may cause scatterer locations and optical path lengths to dynamically change resulting in time dependent intensity modulations of laser speckle. The rate of laser speckle modulation is dependent on the extent of motion of suspended scatterers, which is in turn influenced by viscoelasticity of the medium. Consequently, in a NCFA, due to the relatively low viscosity of lipid, endogenous scatterers within the compliant necrotic core exhibit more rapid Brownian motion compared to the stiffer fibrous regions of the plaque.
Since scatterer motion can govern the modulation of laser speckle, the measurement of temporal intensity variations of laser speckle patterns provides information about the viscoelastic properties of the plaque. Using these principles, it has been successfully demonstrated that the measurement of intensity modulations of time-varying laser speckle patterns provides a highly sensitive technique for evaluating atherosclerotic plaques.36 
While the measurement of composite plaque stability metrics using LSI is invaluable, the opportunity to obtain these measurements is gated by the feasibility of conducting LSI in the coronary vasculature in vivo. Key technical challenges exist in developing an intracoronary LSI device that allows rapid imaging of long coronary segments in the presence of blood flow, while retaining adequate motion stability over the cardiac cycle.
Accordingly, there may be a need to overcome at least some of the deficiencies described herein above.